Restenosis post-coronary dilation is a common disease of iatrogenic etiology that occurs as a direct consequence of arterial injury induced at the time of angioplasty. In the United States, over 500,000 coronary angioplasty procedures are performed annually and this number has been increasing steadily. Despite technical advances and multiple pharmacologic interventions, most studies have found that the incidence of angiographic restenosis remains in the range of 40%. The presenting symptom in the majority of patients with restenosis is exertional angina. Although clinical evidence for restenosis (MI, coronary revascularization, or recurrent angina) may vary from one study to another, clinical restenosis is generally seen in 25 to 35% of the patients within 6 months of their procedure (Circulation 1992; 86:100-110). Restenosis is a time-limited event. Serial angiographic follow-ups have shown that restenosis is most prevalent between 1 and 4 months and rarely occurs beyond 6 months after coronary angioplasty (J Am Coll Cardiol 1988; 12:616-23). The most common treatment strategy for restenosis is repeat angioplasty.
In the past decade, research on prevention of restenosis with pharmacological agents has been almost uniformly disappointing, except for some positive findings with a few drugs yielding conflicting results. The classes of agents tested in a placebo-controlled, randomized study have included antithrombotic agents, fish oil, calcium channel blockers, angiotensin-converting enzyme inhibitors, lipid-lowering agents, steroids, other antiproliferative agents, and magnesium.
Several studies have examined the efficacy of other methods of percutaneous revascularization in the prevention or the treatment of coronary restenosis. Such modalities include: directional and rotational atherectomy, excimer laser-assisted angioplasty, cutting-balloon angioplasty, heat-generating angioplasty devices and coronary stenting.
Other than coronary stenting, no other percutaneous revascularization procedure offers demonstrated advantage over conventional PTCA in preventing or limiting recurring restenosis. Although stent implantation may, in some patients (de novo lesion, native coronary artery with a reference diameter larger than 3.0 mm) prove beneficial (N Engl J Med 1994; 331:489-495) (N Engl J Med 1994; 331:496-501), its clinical or angiographic superiority in vessels smaller than 3.0 mm in diameter has never been shown (Semin Intervent Cardiol 1996; 1:255-262).
Our understanding of the pathophysiology of restenosis has been steadily improving. Once believed to be initiated by an early thrombotic phenomenon, restenosis has been considered in the past 7 years essentially a proliferative process taking place in the weeks following angioplasty at the site of arterial injury. Cytologic analyses of post mortem and atherectomy samples have revealed that smooth muscle cells are the predominant cells responsible for this hyperplastic response. One possible explanation for the negative results with the pharmacologic studies aimed at reducing neointimal hyperplasia is that these strategies targeted the wrong mechanism.
More recently, animal and clinical studies have begun to question the predominant role of cellular proliferation in restenosis and indicate that arterial remodeling is, in fact, an important aspect of the restenosis process (Circulation 1994; 89:2809-15). Inadequate vascular remodeling has been described not only after coronary balloon angioplasty but also after directional and rotational atherectomy and laser angioplasty (Circulation 1996; 94:35-43). Arterial remodeling is defined as a change in total arterial or external elastic membrane (EEM) cross-sectional area (CSA) over time. Arterial remodeling can be bi-directional. Adaptive positive arterial remodeling (an increase in arterial CSA) may represent a compensatory response of blood vessels to hemodynamic stress, arterial injury, and cellular proliferation. Adaptive arterial remodeling has first been described in early coronary artery atherosclerotic disease process (N Engl J Med 1987; 316:1371-5). Adaptive positive arterial remodeling in non-instrumented arteries prevents the reduction in lumen dimensions until plaque occupies 20% to 40% of the CSA within the internal elastic membrane (20% to 40% cross-sectional narrowing or plaque burden) (Am J Cardiol 1997; 80:1408-13). Alternatively, pathologic negative arterial remodeling (a decrease in arterial CSA or chronic arterial constriction) has been shown to contribute to lumen compromise in chronic, focal de novo stenosis in femoral and coronary arteries (Circulation 1995; 91:1444-9 and Circulation 1997; 95:1791-8).